BC Cancer Protocol Summary for Curative Combined Modality Therapy for Carcinoma of the Anal Canal using Mitomycin, Capecitabine and Radiation Therapy Protocol Code: GICART Tumour Group: Gastrointestinal Contact Physician: GI Systemic Therapy ELIGIBILITY: . Squamous cell or Cloacogenic carcinoma of the anal canal . T any, N any, M0 . ECOG performance status less than or equal to 2 . Adequate marrow reserve (ANC greater than or equal to 1.5 x 109/L, platelets greater than 100 x 109/L) . Adequate renal (Creatinine less than or equal to 1.5 x ULN) and liver function (bilirubin less than or equal to 26 micromol/L; AST/ Alkaline Phosphatase less than or equal to 5 x ULN) EXCLUSIONS: . Uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the preceding 6 months, serious uncontrolled cardiac dysrhythmia . Known HIV positive TESTS: . Baseline: CBC, differential & and platelets, calculated creatinine clearance, ALT, Alk Phos, Bilirubin . During treatment: CBC, differential and platelets, creatinine weekly . For patients on warfarin, weekly INR during capecitabine therapy until stable warfarin dose established, then INR prior to each cycle. After treatment: CBC, differential and platelets, creatinine weekly for 2 weeks after chemoradiation PREMEDICATIONS: . Treatment is high to moderately emetogenic. See SCNAUSEA protocol. BC Cancer Agency Protocol Summary GICART Page 1 of 6 Revised: 1 June 2021 (Tests Revised) Warning: The information contained in these documents are a statement of consensus of BC Cancer Agency professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at your own risk and is subject to BC Cancer Agency's terms of use available at www.bccancer.bc.ca/legal.htm TREATMENT: Drug Dose BC Cancer Administration Guideline mitomycin 10 mg/m2 on Day 1 Week 1 and IV push on Day 29 Week 5 (Week 5 mitomycin is optional) (Maximum dose = 20 mg) PO with food. Second dose capecitabine* 825 mg/m2 BID on each RT day (Days 1-5, 8- 12, 15-19, 22-26, 29-33 and continue until last should be taken 10-12 hours after day of RT) the first dose Note: capecitabine treatment is completed on the last day of RT (Total daily dose=1650 mg/m2) *Capecitabine is available as 150 mg and 500 mg tablets (refer to Capecitabine Suggested Tablet Combination Table for dose rounding). Week 1 2 3 4 5 6 Radiation X X X X X 1/2 therapy** capecitabine Continue X X X X X until last Days 1-5 Days 8-12 Days 15-19 Days 22-26 Days 29-33 day of RT mitomycin X X Day 29 Day 1 (mitomycin optional) ** Radiotherapy: 50.4 Gy in 28 fractions (over 5 ½ weeks, no gap) DOSE MODIFICATIONS: 1. Hematological ANC (x 109/L) Platelets (x 109/L) Mitomycin Dose Greater than or equal to 1.5 and Greater than or equal to 100 100% Less than 1.5 or Less than 100 Delay treatment ANC Platelets 1st Event 2nd Event 3rd Event 4th Event (x 109/L) (x 109/L) Capecitabine Capecitabine Capecitabine Capecitabine Dose Dose Dose Dose greater than or and greater 100% 100% 100% 100% equal to 1.5 than or equal to 75 1 – 1.49 or 50-74.9 delay* then delay* then delay* then discontinue 100% 75% 50% 0.5-0.99 or 25-49.9 delay* then delay* then discontinue discontinue 75% 50% less than 0.5 or less than discontinue or discontinue discontinue discontinue 25 delay* then 50% *Delay until ANC greater than or equal to 1.5 x 109/L and platelets greater than or equal to 75 x 109/L BC Cancer Agency Protocol Summary GICART Page 2 of 6 Revised: 1 June 2021 (Tests Revised) Warning: The information contained in these documents are a statement of consensus of BC Cancer Agency professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at your own risk and is subject to BC Cancer Agency's terms of use available at www.bccancer.bc.ca/legal.htm 2. Hand-Foot Skin Reaction: Capecitabine If only chemotherapy is interrupted due to toxicity, retain the original stop and start dates (i.e., do not make up for missed doses when treatment is resumed). Grade Hand-Foot Skin Reaction 1st Event 2nd Event 3rd Event 4th Event Dose Dose Dose Dose Skin changes with discomfort (eg, numbness, dysesthesia, 1 100% 100% 100% 100% paresthesia, tingling, erythema) not disturbing normal activities Skin changes (eg, erythema, delay* then delay* then delay* then 2 swelling) with pain affecting discontinue 100% 75% 50% activities of daily living Severe skin changes (eg, moist desquamation, ulceration, Discontinue blistering) with pain, causing delay* then 3 or delay* discontinue discontinue severe discomfort and inability 75% then 50% to work or perform activities of daily living *Stop treatment immediately and delay until resolved to grade 0-1 3. Other Non-Hematological Toxicity: If only chemotherapy is interrupted due to toxicity, retain the original stop and start dates (i.e., do not make up for missed doses when treatment is resumed). Toxicity Criteria Grade Diarrhea Nausea and Vomiting Stomatitis 0-1 Increase of 2-3 stools/day 1 episode/day but can eat Painless ulcers, erythema or nocturnal stools or mild soreness 2 Increase of 4-6 stools/day 2-5 episodes/day; intake Painlful erythema, edema or nocturnal stools decreased but can eat or ulcers but can eat 3 Increase of 7-9 stools/day 6-10 episodes/day and Painful erythema, edema or incontinence, cannot eat or ulcers and cannot eat malabsorption 4 Increase of 10 or more 10 episodes or more per Mucosal necrosis, requires stools/day or grossly day or requires parenteral parenteral support bloody diarrhea; may support; dehydration require parenteral support; dehydration Dose Adjustment Toxicity 1st Event 2nd Event 3rd Event 4th Event Grade Dose Dose Dose Dose 0-1 100% 100% 100% 100% 2 delay* then 100% delay* then 75% delay* then 50% discontinue 3 delay* then 75% delay* then 50% discontinue discontinue 4 discontinue or discontinue discontinue discontinue delay* then 50% *Stop treatment immediately and delay until toxicity resolved to grade 0-1 BC Cancer Agency Protocol Summary GICART Page 3 of 6 Revised: 1 June 2021 (Tests Revised) Warning: The information contained in these documents are a statement of consensus of BC Cancer Agency professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at your own risk and is subject to BC Cancer Agency's terms of use available at www.bccancer.bc.ca/legal.htm 4. Hepatic dysfunction: Dose modification may be required. Capecitabine has not been studied in severe hepatic dysfunction. 5. Renal dysfunction A. Capecitabine Creatinine Clearance mL/min Dose greater than 50 100% 30-50 75% less than 30 0% Cockcroft-Gault Equation: Estimated creatinine clearance: = N (140-age) wt (kg) (mL/min) ------------------------------------–– Serum creatinine (micromol/L) N = 1.23 male N = 1.04 female B. Mitomycin: Dose modification required for mitomycin if severe renal dysfunction (creatinine clearance less than 12 ml/min) (BC Cancer Drug Manual). PRECAUTIONS: Capecitabine: 1. Patients may experience severe toxicity while receiving concurrent Chemotherapy and Radiation Therapy. Capecitabine and radiation may have to be interrupted until toxicity has improved to grade 1 or less. The dose of capecitabine should be adjusted according to the tables upon restarting chemoradiation. It is important that the patient receive the full Radiation Therapy component. The major toxicity during concurrent Chemotherapy and Radiation Therapy is severe diarrhea, usually during week 4. The patient should be monitored to ensure that dehydration does not occur. 2. Hand-foot syndrome may also occur and should be monitored with treatment interruption and dose reductions as indicated in the dose modification section. 3. Myocardial ischemia and angina occurs rarely in patients receiving fluorouracil or capecitabine. Development of cardiac symptoms including signs suggestive of ischemia or of cardiac arrhythmia is an indication to discontinue treatment. If there is development of cardiac symptoms patients should have urgent cardiac assessment. Generally re-challenge with either fluorouracil or capecitabine is not recommended as symptoms potentially have a high likelihood of recurrence which can be severe or even fatal. Seeking opinion from cardiologists and oncologists with expert knowledge about fluorouracil / capecitabine toxicity is strongly advised under these circumstances. The toxicity should also be noted in the patient’s allergy profile. BC Cancer Agency Protocol Summary GICART Page 4 of 6 Revised: 1 June 2021 (Tests Revised) Warning: The information contained in these documents are a statement of consensus of BC Cancer Agency professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at your own risk and is subject to BC Cancer Agency's terms of use available at www.bccancer.bc.ca/legal.htm 4. Diarrhea: Patients should report mild diarrhea that persists over 24 hours or moderate diarrhea (4 stools or more per day above normal, or a moderate increase in ostomy output).